There is a substantial gap in understanding how prevalence of advanced adenomas leads to incidence and mortality of colorectal cancer and how such causality differs in age and gender. Continued existence of this gap represents an important problem because until it is filled, selection of preferable colorectal cancer screening strategies for distinct population subgroups characterized by age category and gender that lead to cost-effective patient-centered colorectal cancer screening will remain largely unachievable. The long-term goal is to determine whether CRC screening may be tailored based primarily on the predicted prevalence of advanced adenomas for individual patients who do not present other CRC risks. The objective in this particular application is to predict, via discrete-event microsimulation, CRC incidence, mortality, and cost-effectiveness of applying recommended screening strategies to distinct age-gender subgroups. The differences in CRC risk by age and gender have recently been shown in a number of clinical observational studies. However, they have not been incorporated in screening guideline development by any guideline organization. The central hypothesis is that screening recommendations tailored by age and gender are more effective and cost- effective than non-tailored strategies. This hypothesis has been formulated on the basis of several recent studies describing age- and gender-specific prevalence of advanced adenomas, including our preliminary study. The rationale for the proposed research is that by incorporating screening colonoscopy clinical data into CRC natural history modeling and comparing incremental cost-effectiveness ratios among representative screening strategies, we can make convincing age- and gender-based policy recommendations. Ensured by the strong track record of each member on our team and our successful collaborations in the past, this hypothesis will be tested by pursuing two specific aims: 1) Estimate the age- and gender-specific parameters of the natural history of CRC, e.g., adenoma incidence and progression rates; and 2) Evaluate the comparative effectiveness and cost-effectiveness of representative screening strategies for age- and gender-based population subgroups. Under the first aim, a discrete-event simulation model that mimics the age- and gender- dependent CRC natural history will be calibrated with screening colonoscopy observational data available to us. Under the second aim, relative costs, risks, and benefits will be estimated with the tailored simulation, obtained under the first aim, among representative screening strategies for distinct age-gender subgroups. The approach in the proposed research is innovative, because it applies discrete-event simulation to conduct more complex modeling of CRC natural history and more detailed modeling of screening strategies. The proposed research is significant, because it will provide the knowledge required to lead to individualization of CRC screening. Ultimately, such knowledge has the potential to inform the guideline development of patient- centered CRC screening that will help to delivery more efficient and cost-effective CRC prevention and control.